This is an application for the competitive renewal of the 21st through the 25th year of a training program to provide intensive laboratory training for physicians as well as for Ph.D. We emphasize training of physicians in basic biomedical research, as there are a decreasing number of physicians that enter research careers. The program is a combined effort of several departments at UCSF including the Depts. of Medicine, Pediatrics, Laboratory Medicine, Biochemistry & Biophysics, the Cardiovascular Research Institute and the Cancer Research Institute. Most of the faculty advisors are professors and all have active program research and experience in training fellows. The themes embrace investigations into basic and translational research in hematology, oncology and gene expression. The major topics are: hematological studies including red cell, white cell, platelets and premature distribution of red cells in hematologic anemia, molecular basis of diagnosis and treatment ofhemoglobinopathies and thalassemias, families of receptors on leucocytes, T cell differentiation and response to antigens, megakarocytopoieses, thrombin receptors and a family pf protease activated protein-couple receptors, and signal transduction in hematopoietic cells. Also, prenatal and postnatal treatment of single gene disorders such as thalassemia, and stem cell transplantation in utero will be studied. Two programs in hematologic malignancies are the role of chromosomal translocation in acute promyelocytytic leukemia and the relation between neurofibromatosis 1 and leukemia. Oncological studies include the genetic and biochemical mechanism of tumor progression and growth, oncogene induced apoptosis and therapeutic intervention of cancer cells through signal transduction pathways. Also, studies on the synthesis and function of telomeres and the mechanism of telomerase action as well as the molecular and physiologic pathways of leptin action will be offered. In addition to many of the tools in molecular and cell biology, the trainees will also learn new technologies such as microarrays and comparative genomic hybridization. UCSF has a host of formal lectures and seminars for the trainees including those in the Program in Biological Sciences (PIBS), the Program in Biomedical Sciences (BMS) and the Molecular Medicine Training Program. Thus, the trainees will be exposed to a rich, intellectual and educational environment.